1630 BRITISH MEDICAL JOURNAL VOLUME 284 29 MAY 1982 cluding medical care and research in their for aspirin. Discontinuations for lack of efficacy for reporting in detail the side effects en- own countries. were equivalent for benoxaprofen and aspirin but countered while treating various arthritides D HADDOCK twice as high for ibuprofen. with benoxaprofen (8 May, p 1365). We have all The experimental work reported by Dr Colin Liverpool School of Tropical Medicine, met similar problems to a greater or lesser L3 Hindson and others (p 1368) confirms the findings Liverpool 5QA of Kligmant and Griest2 in the USA and Ferguson extent. et a13 in the UK. They conclude that phototoxicity When this drug was released on the market due to benoxaprofen is a predictable side effect exactly two years ago great publicity was given and is related to exposure to both the drug and to in the general press, and claims were made Side effects of benoxaprofen ultraviolet A radiation. With appropriate measures, as if a "cure" for arthritis had been found. The exposure to UVA can be minimised. result has been that we have been overwhelmed SIR,-The BMJ of 8 May contains three The report by Drs Hugh McA Taggart and by our patients (with paper cuttings in their articles concerning side effects ofbenoxaprofen. Joan M Alderdice (p 1372) of fatalities in elderly taking benoxaprofen is remarkable for the hands) for prescription of this drug. Drs J P Halsey and N Cardoe (p 1365) report patients I hope this article will be a side effects encountered in a study of 300 striking concentration of six deaths in one practice. lesson to the No jaundice and no deaths due to hepatic failure general press when a new drug appears, not to patients treated with benoxaprofen. The side raise false hopes in the describe are qualitatively similar were reported in approximately 2200 carefully minds of the sufferers effects they followed patients who participated in clinical of this terrible disease. to those previously reported for the drug, but trials in the USA. The Inman report did not their incidence is considerably higher than mention the occurrence of jaundice. It is now M A WAJED has been noted in other studies. For example, estimated that approximately 500 000 patients Hemel Hempstead General they reported that 65-3% of patients had at have received benoxaprofen in the UK. Exclusive Hospital, least one side effect, 28-6% had photo- of the experience of Dr Taggart/Alderdice and of Hemel Hempstead, Herts HP2 4AD sensitivity, 8% onycholysis, and 18% gastro- Goudie et al' (see below), Dista UK has received intestinal side effects. The drug was with- 11 reports of jaundice. Three of these patients drawn in 34-6% of patients because of side died; other drugs and complicating underlying conditions are involved in these deaths, and further SIR,-We would like to clarify one point which effects. They noted that side effects were more investigation is being carried out to define the role in patients over 70 years of age. may be misleading in our article (8 May, frequent of benoxaprofen. p 1368). We demonstrated phototoxicity in all Recently Dr William Inman (personal com- Several clinical and pathological features of patients whom we phototested. To date, we munication) at the Drug Surveillance Unit at the Drs Taggart and Alderdice's patients are note- have investigated 14 Caucasian who University of Southampton circulated to general worthy. All of the patients were over 80 years of patients practitioners the results of a postmarketing age, and all were women. One patient had an were receiving benoxaprofen for rheumatoid surveillance study of benoxaprofen involving 5000 enlarged liver six months before benoxaprofen was conditions and who presented with no evidence patients. In those trials "events" were recorded in prescribed. All were on other medications, including of skin disease. In all 14 subjects we observed 46% of patients: 13% had cutaneous events (4% paracetamol in three. A confusing observation was immediate responses of erythema and flaring, photosensitivity); 1-5% had onycholysis; and 11% that at necropsy the major finding was intrahepatic together with subjective sensations of itching gastrointestinal events. cholestasis, a condition which is very rarely fatal. and burning. Clinical trial data accumulated in North America Decreased renal function was present in some of Although the study of Dr Halsey and Dr in over 2200 patients studied for up to three years the patients prior to therapy, and renal failure was a Cardoe (8 p showed that drug-related side effects occurred in a prominent feature of the clinical course. May, 1365) reported photo- total of 29% of patients (events of uncertain B M Goudie et a14 recently reported the sensitivity side effects in 28-6% of patients causality occurred in a further 27%' of patients): occurrence of jaundice in three patients on taking benoxaprofen, we believe there is the phototoxicity, onycholysis, or both in about 15%; benoxaprofen. All were women and over 70 years potential for photosensitivity reactions in a and gastrointestinal complaints in 15%. of age. Two recovered when benoxaprofen was much higher proportion of patients. These numbers illustrate the problems en- discontinued; one died of bronchopneumonia. countered in attempting to compare the incidence Jaundice has been reported with most of the other BRIAN DIFFEY in available non-steroidal anti-inflammatory drugs. of side effects reported various trials. The Regional Medical Physics Department, differences noted may be related to population More detailed information will be required to Dryburn Hospital, differences, but probably the most important assess the significance of the cluster of fatal cases Durham DH1 5TW factors are the method by which side effects are reported by Drs Taggart and Alderdice, but it is COLIN HINDSON sought and the manner in which they are evaluated. clear that jaundice associated with benoxaprofen Dermatology Department, Drs Halsey and Cardoe alluded to this problem is a rare event. Royal Infirmary, in interpretation when they noted that in their The increased incidence of minor side Sunderland SR2 7JE study the incidence of side effects may have been artificially high owing to coincidental non-drug effects in elderly people reported by Drs related medical conditions. They also pointed out Halsey and Cardoe, the jaundice in elderly that side effects have been reported in 150" of patients reported by Drs Taggart and Alder- dice and by Goudie et al, and the pharmaco- SIR,-At first sight, the BMJ of 8 May might patients with rheumatoid arthritis taking placebo, make any rheumatologist cringe with shame. suggesting the difficulty of assigning a causal kinetic data showing a prolonged half life of azapropazone relationship between administration of a drug and benoxaprofen in elderly patients with impaired Drug-induced lupus (p 1358), a possible side effect. of interactions (p 1373), and polyarthritis due to renal function emphasises the importance (pl373) are all mentioned. But it is To gain a true picture of the incidence of side using a reduced dose in such patients. Pre- quinidine effects with different drugs it is necessary to the three papers on benoxaprofen toxicity conduct a study taking all necessary steps to scribing information supplied by Lilly (Dista) That Dr J P attention to this which demand attention. by control bias-for example, random entry and specifically calls important Halsey and Dr N Cardoe (p 1365) is a straight- double-blind design. Such studies were done in consideration. Elderly patients should be is observed forward record of events: drug toxicity in the clinical trials of benoxaprofen sponsored by followed carefully, and if jaundice The total incidence of toxic reactions Eli Lilly and Company. In those trials photo- benoxaprofen should be promptly dis- practice. sensitivity and onycholysis were identified as side continued. was very high, but we need to see the same effects of benoxaprofen but not of aspirin or reporting system used for other drugs-that is, ibuprofen. The incidence of gastrointestinal side W IAN H SHEDDEN a control group. What was the incidence of Vice President, Lilly Research effects was similar to that of ibuprofen but about Laboratories toxicity due to other drugs taken singly or in half that observed with aspirin. Unlike the Eli Lilly and Company, combinations under the same conditions ? gastrointestinal side effects, photosensitivity is Indianapolis, Indiana The phototoxic reaction described and dis- generally preventable and can be minimised by cussed in Dr Colin Hindson and colleagues' of to the use of Kligman AM, Kaidbey KH. Eturopean Joutrnal of avoidance exposure sun, protective Rheumnatology and Inflammrnation. 1982 ,5 :127-37. paper (p 1368) can be most uncomfortable clothing, and the use of sunscreen lotions. 2Griest MC, Oxols II, Ridolfo AS, Muus JC. Eu4ropean Drs Halsey and Cardoe comment on the 7ournal of Rheumatology and Inflammation 1982; for patients. We have known about this now with which were withdrawn 5:138-47. for over two years, and the company concerned frequency patients Ferguson J, Addo HA, McG PE, Woodcock KR, from benoxaprofen because of the occurence of Johnson BE, Frain-Bell W. Br J Derm (in press). have issued cards for patients warning them side effects. This gives an incomplete picture. A 4 Goudie BM, Birnie GF, Watkinson G, MacSween how to reduce its frequency. Were any of a is the RNM, Kissen LH, Cunningham NE. Lancet better measure of drug's acceptability 1982 ;i :959. Dr Hindson and colleagues' patients so frequency of drug discontinuance due both to side warned ? effects and to lack of efficacy. In the six-month For the past three or four years it has been controlled trials drug was withdrawn for both reasons in 17`o of benoxaprofen patients, 230' of my practice to ask of pharmaceutical represen- those on ibuprofen, and 25°" of those on aspirin.